THIS IS A SHANNON AWARD PROVIDING PARTIAL SUPPORT FOR THE RESEARCH PROJECTS THAT FALL SHORT OF THE ASSIGNED INSTITUTE'S FUNDING RANGE BUT ARE IN THE MARGIN OF EXCELLENCE. THE SHANNON AWARD IS INTENDED TO PROVIDE SUPPORT TO TEST THE FEASIBILITY OF THE APPROACH; DEVELOP FURTHER TESTS AND REFINE RESEARCH TECHNIQUES; PERFORM SECONDARY ANALYSIS OF AVAILABLE DATA SETS; OR CONDUCT DISCRETE PROJECTS THAT CAN DEMONSTRATE THE PI'S RESEARCH CAPABILITIES OR LEAD ADDITIONAL WEIGHT TO AN ALREADY MERITORIOUS APPLICATION. THE APPLICATION BELOW IS TAKEN FROM THE ORIGINAL DOCUMENT SUBMITTED BY THE PRINCIPAL INVESTIGATOR. Alcoholism represents a major medical as well as an economic and social burden in our society. One of the serious consequences of chronic alcohol use is the development of physical dependence and the possibility of experiencing a life-threatening withdrawal syndrome. The natural course of the disease is episodic in that, invariably, periodic interruptions in chronic alcohol consumption occur. Thus, not only is experience with a characteristic withdrawal syndrome common in the alcoholic, but multiple such occurrences are likely. Among other variables, prior episodes of ethanol (EtOH) withdrawal may increase the severity of future withdrawal reactions, an effect that is viewed as being somewhat akin to a "kindling-like" phenomenon. Both clinical and experimental evidence have demonstrated a progressive intensification of the withdrawal syndrome following repeated episodes of EtOH intoxication and withdrawal. The focus of this proposal is directed toward using an established animal model of potentiated EtOH withdrawal to begin to probe for neurochemical mechanisms underlying the phenomenon. As an initial step in the search for underlying mechanisms, the role of the GABAa and NMDA receptor systems will be examined in potentiated EtOH withdrawal. The general hypothesis to be tested is that decreased GABAa receptor activity and increased NMDA receptor activity progressively intensify with each successive EtOH withdrawal episode and the magnification of these changes is ultimately manifested as an observed potentiation of withdrawal seizures following repeated EtOH withdrawal experience. Studies proposed in this application are designed to test this hypothesis by comparing both behavioral sensitivity and neurochemical changes in animals with multiple or single EtOH withdrawal experience. Altered behavioral sensitivity (measured as chemoconvulsant seizure threshold dosage) to drugs active at the GABAa and/or NMDA receptor complexes will provide indirect support for the general hypothesis while more direct evidence for the involvement of these receptor systems will be obtained by measuring sensitivity to drug- induced modification of GABAa receptor-operated chloride (36C1-) influx, as well as radioligand binding parameters at each of the receptor complexes. Taken together, the proposed work will provide important information about the potential role of the GABAa and NMDA receptor systems in mediating potentiated EtOH withdrawal associated with repeated withdrawal experience. Moreover, results from these studies may provide clinically- relevant insight regarding more effective pharmacotherapy strategies for treating EtOH withdrawal.